Condensation-dependent interactome of a chromatin remodeler underlies tumor suppressor activities

TL;DR

A mutation in the CHD1 chromatin remodeler disrupts its ability to form condensates, leading to abnormal gene expression and promoting cancer.

Contribution

The study identifies how a specific CHD1 mutation impairs condensate formation, linking it to tumor suppressor activity and cancer progression.

Findings

The E1321 frameshift mutation in CHD1 truncates its C-terminus, preventing condensate formation and promoting tumorigenesis.

CHD1 condensates require H3K4me3-modified nucleosomes and RNA to regulate gene expression at active promoters.

MLL mutations frequently co-occur with CHD1 mutations, suggesting a shared pathway in cancer development.

Abstract

Chromatin remodelers are vital for cellular functions like transcription by modulating nucleosome accessibility. Although biological condensates regulate these processes, the contribution of chromatin remodelers to condensation mechanisms remains poorly understood. Here, we examine the role of the E1321 frameshift mutation in CHD1, a chromatin remodeler, which is often targeted in cancers. This mutation truncates CHD1’s C-terminus, leading to an oncogenic transcriptome and promoting tumorigenesis. This is due to the loss of an intrinsically disordered region (IDR) crucial for forming CHD1 condensates. These condensates are facilitated by the presence of H3K4me3-modified nucleosomes and RNA, guided to active promoters to regulate gene expression. Furthermore, CHD1 condensates contain long noncoding RNA and histone-modifying proteins, revealing an integral role for CHD1 condensates in epigenetic regulation. Among these components, MLL mutations frequently co-occur with CHD1 mutations in various cancers, suggesting a shared pathway in cancer development. These findings underscore the importance of chromatin remodeler condensation as a regulatory hub in various cellular processes and tumor suppression.

This study reveals how a cancer-associated mutation in CHD1 leads to the loss of its C-terminal intrinsically disordered region, disrupting condensate formation. This impairment causes improper genome distribution and gene expression, driving cancer development.

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